Submissions for variant NM_000256.3(MYBPC3):c.3641G>A (p.Trp1214Ter)

dbSNP: rs730880597

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158249	SCV000208184	pathogenic	not provided	2013-08-05	criteria provided, single submitter	clinical testing	p.Trp1214Stop (TGG>TAG): c.3641 G>A in exon 33 of the MYBPC3 gene (NM_000256.3). The Trp1214Stop mutation in the MYBPC3 gene has been reported in an Indian male patient with familial HCM who also harbored another mutation in the MYH7 gene (Bashyam M et al., 2012). The mutation was absent from 100 ethnically matched control individuals. Trp1214Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Trp1214Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217718	SCV000271411	pathogenic	Hypertrophic cardiomyopathy	2015-11-13	criteria provided, single submitter	clinical testing	The p.Trp1214X variant in MYBPC3 has been previously reported in 1 individual wi th HCM (Bashyam 2011) and was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 1214, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact of the variant.
Invitae	RCV000217718	SCV002244226	pathogenic	Hypertrophic cardiomyopathy	2022-11-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 181015). This premature translational stop signal has been observed in individual(s) with familial hypertrophic cardiomyopathy (PMID: 21959974, 23299917, 32746448, 32841044). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1214*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).